Background: Vascular dementia (VAD) is the second most common type of dementia lacking effective treatments. Pentoxifylline (PTX), a nonselective phosphodiesterase inhibitor, displays protective effects in multiple cerebral diseases. In this study, we aimed to investigate the therapeutic effects and potential mechanisms of PTX in VAD. Methods: Bilateral common carotid artery stenosis (BCAS) mouse model was established to mimic VAD. Mouse behavior was tested by open field test, novel object recognition test, Y-maze and Morris water maze (MWM) tests. Histological staining, magnetic resonance imaging (MRI) and electron microscopy were used to define white matter integrity. The impact of PTX on microglia phagocytosis, peroxisome proliferator-activated receptors-γ (PPAR-γ) activation and Mer receptor tyrosine kinase (Mertk) expression was assessed by immunofluorescence, western blotting and flow cytometry with the application of microglia-specific Mertk knockout mice, Mertk inhibitor and PPAR-γ inhibitor. Results: Here, we found that PTX treatment alleviated cognitive impairment in novel object recognition test, Y-maze and Morris water maze tests. Furthermore, PTX alleviated white matter injury in corpus callosum (CC) and internal capsule (IC) areas as shown by histological staining and MRI analysis. PTX-treatment group presented thicker myelin sheath than vehicle group by electron microscopy. Mechanistically, PTX facilitated microglial phagocytosis of myelin debris by up-regulating the expression of Mertk in BCAS model and primary cultured microglia. Importantly, microglia-specific Mertk knockout blocked the therapeutic effects of PTX in BCAS model. Moreover, Mertk expression was regulated by the nuclear translocation of PPAR-γ. Through modulating PPAR-γ, PTX enhanced Mertk expression. Conclusions: Collectively, our results demonstrated that PTX showed therapeutic potentials in VAD and alleviated ischemic white matter injury via modulating Mertk-mediated myelin clearance in microglia.

Recently, it has been suggested that molecular hydrogen (H₂) can selectively reduce the levels of hydroxyl radicals (.OH), and ameliorate oxidative and inflammatory injuries to organs in global cerebral ischemia reperfusion models. Global cerebral ischemia/reperfusion (I/R) can induce a sudden activation of inflammatory cytokines and later influence the systemic immunoreactivity which may contribute to a worse outcome. Regulatory T cells (Tregs) are involved in several pathological aspects of cerebral I/R. In addition, miRNA took part in the processes of cellular response to hypoxia. Since the expression of a specific set of miRNA called “hypoxamirs” is upregulated by hypoxia. Therefore, the aim of this study was to analyze the effect of HRS on I/R inducing cerebral damage, Tregs, and specific miRNA. Our results showed that rats undergone global cerebral I/R and treated with HRS have milder injury than I/R animals without HRS treatment. miR-210 expression in the hippocampus of the I/R group at 6, 24 and 96 h after reperfusion was significantly increased at each time point, while its expression in the group treated with HRS was significantly decreased. In addition, Tregs number in group I/R was decreased at each time points, while its number in the group treated with HRS was increased at 24 and 96 h after reperfusion. We focus on the relationship among Tregs, TGF-β1, TNF-α and NF-κB at 24 h, and we found that there is a high correlation among them. Therefore, our results indicated that the brain resuscitation mechanism in the HRS-treated rats may be related with the effect of upregulating the number of Treg cells.

Spread of local anaesthetic solution in the paravertebral space after erector spinae plane block (ESPB) is variable. We evaluated whether paravertebral spread of local anaesthetic is affected by patient position after ESPB. We randomised 84 patients to receive ESPB at T₇ with a mixture of 0.375% ropivacaine and radiocontrast dye (30 ml). Participants were positioned supine, prone, or lateral for 30 min after ESPB before computed tomography scanning. The primary outcome was paravertebral space local anaesthetic spread, with secondary assessments of craniocaudal spread and distribution to neural foramina, and intercostal and epidural spaces. Loss of sensation to cold was recorded. Local anaesthetic-contrast mix reached the paravertebral space, intercostal space, and neural foramina in 96.5%, 94.2%, and 77.9% of individuals, respectively. Epidural space spread occurred in 20 cases. Prone positioning consistently allowed paravertebral and intercostal spread in all patients, with more thoracic level spread compared with supine positioning (5.0 [1.9] vs 3.1 [1.7], difference [95% confidence interval, CI]: 1.9 [0.8-3.0] levels, P<0.001 for paravertebral space spread; 2.8 [1.9] vs 1.4 [1.4], difference [95% CI] levels: 1.4 [0.4-2.5], P=0.004 for neural foramina spread; 4.3 [1.3] vs 3.2 [1.5], difference [95% CI] levels: 1.0 [0.1-1.9], P=0.019 for intercostal space spread). Local anaesthetic-contrast extended to the intercostal space further in the prone than in the lateral position group (4.3 [1.3] vs 2.6 [1.5] thoracic levels, difference [95% CI]: 1.7 [0.8-2.6], P<0.001). Sensory block in ventral dermatomes was variable in all participants. Prone positioning after ESPB significantly enhanced local anaesthetic-contrast spread to the paravertebral space, intercostal space, and neural foramina, suggesting that gravity plays a substantial role in spread. Clinical Trials.gov (NCT06142630).